PEDIATRIC ONCOLOGY SUBCOMMITTEE OF THE ONCOLOGIC DRUGS ADVISORY COMMITTEE

mc SGDEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION PEDIATRIC ONCOLOGY SUBCOMMITTEE OF THE ONCOLOGIC DRUGS ADVISORY COMMITTEE Tuesday, March 4, 2003 8:36 a.m MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc ACS Building Center for Drug Evaluation and Research 5630 Fishers Lane Rockville, Maryland MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc P A R T I C I P A N T S Consultants (Voting) Victor M. Santana, M.D., Chairman Thomas H. Perez, M.P.H., Executive Secretary Alice Ettinger, R.N., Association of Pediatric Oncology Nurses Jerry Finklestein, M.D., University of California, Los Angeles Patrick C. Reynolds, M.D., Los Angeles Children's Hospital James Boyett, Ph.D., St. Jude Children's Hospital Henry Friedman, M.D., Duke University Susan Cohn, M.D., Northwestern University Nancy Keene, Independent advocate Oncologic Drugs Advisory Committee Members Jody Pelusi, F.N.P., Ph.D., North Arizona Hematology & Oncology Associates Gregory Reaman, M.D., Children's Hospital National Medical Center, Washington, D.C Guest Speakers (NonVoting) Malcolm Smith, M.D. Cancer Treatment & Evaluation Program, National Cancer Institute, NIH International Guests (NonVoting) Francesco Pignatti, M.D., European Medicinal Evaluation Agency (EMEA) Katherine Cheng, M.D., Medicines Control Agency, U.K Anne MathieuBoue, M.D., Agence Francaise de Securite Sanitaires de Produits de Sante (AFSSAPS) Gilles Vassal, M.D. AFSSAPS, Institut Gustave Roussy, France Harald Schweim, M.D. Bundes Institut fur Arzneimittel und Medizinprodukte (Bfarm) Mark Bernstein, M.D., Health Protection Branch, Canada MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc Industry Guests (NonVoting) Anne Hagey, M.D., Abbott Laboratories Global Oncology Development Group Alan Melemed, M.D., Eli Lilly MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc C O N T E N T S AGENDA ITEM PAGE Call to Order and Introduction Victor M. Santana, M.D., Chair Conflict of Interest Thomas H. Perez, M.P.H., Executive Secretary Welcome Richard Pazdur, M.D., Director, Division of Oncology Drug Products, and Steven Hirschfeld, M.D., Ph.D., Medical Officer, Division of Oncology Drug Products 2 History of Pediatric Labeling Steven Hirschfeld, M.D., Ph.D 20 Case Studies of Pediatric Submission for Oncology Products Anne Zajicek, Pharm.D., M.D 36 Ramzi Dagher, M.D 40 Steven Hirschfeld, M.D., Ph.D 42 Susan Honig, M.D 44 Alla Shapiro, M.D 47 Committee Questions to the Presenters 50 Open Public Hearing 93 Edward J. Allera, B.S. J.D Buchanan & Ingersoll 94 Summary of Abstract Steven Hirschfeld, M.D 103 Discussion of Questions to the Committee 111 [Lunch] Discussion of Questions to the Committee MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 158 mc P R O C E E D I N G S DR. SANTANA: Good morning. We have been convened today by the FDA to give them some specific guidance related to issues of pediatric labeling for oncology products. And as I understand the format today, Dr. Hirschfeld will first give us an overview of the history of labeling as it relates to the FDA and its regulations, and then we will move on to some specific case studies that they want to discuss with us to bring out some issues that hopefully will provide them with further guidance on how to approach this in the pediatric oncology arena. And then we will have later this morning an open public hearing, and I believe so far there is one individual who wishes to address the committee With that, I want to welcome everybody this morning. We have robust representation from some international guests, and we want to welcome them, too, and people from across the border, too, Dr. Bernstein And with that, I will let then Tom read the conflict of interest, and once we're done with the conflict of interest, I want to go around the table and everybody introduce themselves Thank you MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc MR. PEREZ: Thank you. The following announcement addresses the issue of conflict of interest with respect to this meeting and is made a part of the record to preclude even the appearance of such at this meeting The topic of today's meeting is an issue of broad applicability. Unlike issues before a committee in which a particular product is discussed, issues of broader applicability involve many industrial sponsors and academic institutions. All participants have been screened for their financial interests as they may apply to the general topic at hand. Because they have reported interests in pharmaceutical companies, the Food and Drug Administration has granted general matters waivers to the following special government employees which permits them to participate in today's discussions: Drs. James Boyett, Susan Cohn, Ms. Alice Ettinger, Drs. Jerry Finklestein, Henry Friedman, Jody Pelusi, Gregory Reaman, Charles Reynolds, Victor Santana, and Susan Weiner A copy of the waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, Room 12A30 of the Parklawn Building In addition, Ms. Nancy Keene and Dr. Malcolm Smith do not have any current financial interests in pharmaceutical companies; therefore, they do not require a MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc waiver to participate in today's discussion. Because general topics impact so many institutions, it is not prudent to recite all potential conflicts of interest as they apply to each participant. FDA acknowledges that there may be potential conflicts of interest, but because of the general nature of the discussion before the subcommittee, these potential conflicts are mitigated In addition, we would like to disclose that Dr. Anne Hagey owns Abbott stock and other pharmaceutical company stock as part of her mutual funds and 401(k) retirement fund. She also has companygranted stock options. Additionally, she is a fulltime employee of Abbott Labs and a relative is employed by the pharmaceutical company Dr. Alan Melemed is a fulltime employee of Eli Lilly and Company and has parttime employment with Indiana University School of Medicine In the event that the discussions involve any other products or firms not already on the agenda for which FDA participants have a financial interest, the participants' involvement and their exclusion will be noted for the record With respect to all other participants, we ask in the interest of fairness that they address any current or MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc previous financial involvement with any firm whose product they may wish to comment upon Thank you DR. SANTANA: Anybody else who wants to make any disclosure? [No response.] DR. SANTANA: Thank you, Tom Could we start our introductions beginning with the left side of the panel, please? DR. HAGEY: Good morning. Anne Hagey, pediatric oncologist, Abbott Laboratories DR. CHENG: Good morning. I'm Katherine Cheng. I'm from the Medicines Control Agency, which is the U.K. regulatory authority. I'm also a pediatrician by training but not in oncology DR. SCHWEIM: Good morning, everybody. I'm Harald Schweim from the Bfarm in Germany. I'm heading this institute. I'm educated as medicinal chemist and as medicinal informatics DR. VASSAL: Good morning. I am Gilles Vassal, pediatric oncologist and pharmacologist, working in France in a cancer center called Institut Gustave Roussy in Villejuif. I'm in charge of new drug development in MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc pediatric oncology and chairman of the European program called Innovative Therapies for Children with Cancer DR. BERNSTEIN: Mark Bernstein. I'm a pediatric oncologist at the University of Montreal and a Children's Oncology Group member DR. MATHIEUBOUE: Good morning. I'm Anne MathieuBoue from the French agency for evaluation of medicinal products called AFSSAPS. And my background is oncology/internal medicine DR. PIGNATTI: Francesco Pignatti from the European Medicines Evaluation Agency in London. I'm a medical doctor and biostatistician DR. MELEMED: Alan Melemed, pediatric oncologist, Eli Lilly and Company, as well as Indiana University School of Medicine MS. ETTINGER: I'm Alice Ettinger, and I'm a certified pediatric nurse practitioner, New Brunswick, New Jersey DR. BOYETT: James Boyett, biostatistician from St. Jude Children's Research Hospital MR. PEREZ: Tom Perez, executive secretary to this meeting DR. SANTANA: Victor Santana, pediatric oncologist working at St. Jude Children's Research Hospital MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc If we start putting information in other aspects, I would worry that there's too many different places to look for it, and where do youhow would Dr. X sitting in surgery know whether to look on the FDA website or on the product label or in Medline or wherever? If it was in the product label, at least that would be clear DR. HIRSCHFELD: Just before thethese are, again, studies that the FDA has requested as opposed to a summation of all available knowledge DR. SANTANA: Dr. Reaman? DR. REAMAN: And I think this is an opportunity to respond to a particular congressional request to provide information about pediatric studies. And I think it also extends the definition of safety information, because generally these drugs have significant side effects associated with them. And I think it goes to safety to say that a drug that has no activity that's been well studied but does have associated toxicity, I see no problem in putting that in the label and would support it DR. SANTANA: I did hear, though, a couple of committee members kind of opposed to that view. Would it be helpful if we took a vote? I've heard a couple committee members feeling thatI think there's some majority that says some information should be in the label, as you've MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc heard the discussion. But I heard at least two strong statements that say that they would notno information [Inaudible comment off microphone.] DR. SANTANA: Okay DR. HIRSCHFELD: We're soliciting comments, and then we get into the issue of who can vote and who can't vote and whether DR. SANTANA: Okay. I just wanted to DR. HIRSCHFELD: But I appreciate your DR. SANTANA: thinks that we need to resolve this by a vote, we can do it. If you just want to hear both sides of the story, I think you're getting that Dr. Reynolds DR. PAZDUR: And I think they were well founded, i.e., we want to define the population, we want to, you know, be specific when we say it has no activity, you know, it's not just a blanket statement. So I think it's helpful to us DR. SANTANA: Dr. Reynolds? DR. REYNOLDS: I just want to askyou know, I think Greg's comments refining this are very good. I just wanted to clarify if putting that kind of negative data into a label is in any way perceived as burdensome to the industry. And maybe industry could comment on that. Is MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc that extra work for them, in other words? Is that an issue that DR. PAZDUR: Well, we askedI think the important thing that differs this from my previous statements about many negative adult studies, we asked for this. Okay? And, therefore, they got a report back DR. REYNOLDS: So the specific thing that you asked when you specifically put that in. So in essence, then, it isthat's the clarification. It is no real extra work. They have to incorporate that into the label. The work has already been done DR. HIRSCHFELD: Yes, and they would get a six month sales extension on exclusivity, which is not to be trivialized DR. REYNOLDS: Right. I just wanted to clarify that point. Thank you DR. SANTANA: Dr. Vassal? Since you came from so far away DR. VASSAL: Thank you. Just if I come back to Case 4, which illustrates the point, before the request by the FDA, maybe in this label was written the sentence, "Safety and efficacy was not tested or evaluated in children." Right now it's no longer the case. So clearly MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc for me, the safety data acquired in these Phase II studies should be available in the label On the other side, if we consider efficacy, clearly considering the large number of tumor types, especially the case of neuroblastoma, which was earlier stopped because of many, many reasons, I think it's very difficult to say there is no activity because there is maybe not enough data to really demonstrate that there is no activity. So to me, in this situation it would be important to have the safety data clearly available, and the sentence showing that at the moment there is no evidence or not enough evidence of activity, but maybe not detailed on all the different tumor types with not enough data to DR. PAZDUR: I think we hear that clearly, that there has to be some scientific precision and not to make a blanket terminology of no clinical activity in pediatric oncology here DR. SANTANA: And I think Steve did preface his question DR. PAZDUR: And that's really DR. SANTANA: that safety DR. PAZDUR: science. That's not even a regulatory MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc DR. SANTANA: And that safety information would be inherent in this information, too. Okay. Let's move on. I think we did reach a consensus on that, or at least some comments Let's read the last one, then. The following question pertains to the situation where there is no efficacy or safety data available in pediatric patients. And when no efficacy or safety data are available in pediatric patients, consider if a statement that safety and efficacy have not been tested in children be included in the product label My comment to this goes back to a discussion we had earlier this morning, which is the rapidity and timing of the update of the label. I'm concerned that such a blanket statement when there are currently studies that are ongoing that potentially could change the statement once that information becomes available, what is the commitment to turn that around in a reasonable way that the public and the practitioners could be informed that there is now information? So I'm not so worried about the statement. I'm just worried that once you put that statement here in the discussion this morning, that statement may stay there for eternity, and it may no longer be true six months from MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc now. So what is the mechanism to get that taken care of in a time fashion to change it? DR. HIRSCHFELD: Well, the context here would be because we're trying to focus this onwe are asking for data and then what to do with it. If we ask for data and don't get any data DR. SANTANA: There's no data DR. HIRSCHFELD: Yes. What should we do? Should we say there are no data? Or should we say something else? That's the nature of it. It's not to say in the known human experience there are no data. The question is we've made a request for data, there are no data, and we don't foresee data DR. SANTANA: Comments? Dr. Schweim? DR. SCHWEIM: If this situation would occur in Germany, we were forced as an agency to point out this sentence in the package leaflet. We're forced in any cases where there is no data for children available that we do not have any data, there's a special paragraph in the German drug law only for the purpose for children. It's not necessary for pregnant women or other specialized groups of the population. But for children it's necessary. If there is no data, we have to state it out MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc But I would add a further comment. I think the main problem is the update method you have for SPC or package leaflet in the U.S. In our system, we have an automatic update if there is any new data available, and the company is forced to present this data, even if they collect it from the literaturenot only if they collect it from their own clinical trials. And I think if you would have established such an update, automatic update period, this would be a less problematic situation DR. SANTANA: Dr. Finklestein? DR. FINKLESTEIN: It's a twopart question. What do you do now? Say you don't request the information and a drug is submitted and there's no pediatric data, what do you do with the label right now? DR. HIRSCHFELD: We have the default statement, which is safety and efficacy have not beenor safety and effectiveness have not been established DR. FINKLESTEIN: Then why would that default statement not apply to Question 5? DR. HIRSCHFELD: Well, we're just trying to, in effect, parse it out a little finer. The first case, you could have data that exist but someone chooses not to submit it, and we would say that statement, it hasn't been established. Or you could have negative data, and you could MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc say safety and effectiveness have not been established. Or you could have no data. You don't have the ability to distinguish among those possibilities The regulations allow alternate wording, and so we were just requesting some advice from the committee. The default statement we find is perhaps not sufficiently informative, and here's a case where we might be able to adjust that DR. FINKLESTEIN: The second part of the question has to do with a comment from our colleague from Germany. This is the era of Internet and electronic transmission, and what are your plans in terms of updating information so that everyone can obtain it in a morethere's a phrase DR. SANTANA: Timely manner? DR. FINKLESTEIN: Well, friendly manner. There's an Internet phrase you use, virtually effective, concurrently, and all other terminology. In other words, putting it in a DR. SANTANA: Realtime DR. FINKLESTEIN: Yes, realtime. Thank you. Putting it in a label that then gets killed, that's for 1940s. What are your plans now for the year 2003? DR. HIRSCHFELD: That's a broader agency policy question, but it's an issue that I know the Commissioner has MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc expressed particular interest in. There are some initiatives underway, and it's going to require cooperation among investigators getting data to the pharmaceutical sponsors and pharmaceutical sponsors getting the data to the FDA. So it's going to be a system solution DR. SANTANA: Dr. Cohn? And then Dr. Hagey DR. COHN: I was just going to follow up on your point, which was that things change. And so to say that there's no data available at this point in time won't necessarily be correct a couple weeks from now. But since you have dates on your labels, can't you say as of this date no safety and efficacy data are available, and then everybody will know what the last update is, and hopefully eventually it will become realtime and, you know, you'll have it as of last Monday instead of as of six years ago DR. SANTANA: My comment was also related to a comment I heard earlier this morning from Richard about a specific drug that hadn't been updated for 20 years, although there was a lot of information. So I wanted to press the issue that in pediatric oncology, if there are studies that need to be updated that are providing information, that at least in this arena we establish a mechanism where that doesn't take us 20 years to get it back in the label. That was my point. It's just a comment to MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc the agency of the importance, at least in this field, if we're going to make these kind of statements in pediatric oncology where the focus is right now, that we be cognizant of the need to move very quickly so that the label reflects what actually has happened DR. PAZDUR: And it can. You know, I didn't mean that it's a static document that never changes. Obviously we get updates on our INDs, which the European system doesn't even have, looking atright? You guys don't have an IND mechanism? [Inaudible comment off microphone.] DR. PAZDUR: Okay. So, you know, we get regular and routine safety updates. We have trials that are coming in, and obviously the product label would be changed with those trials that the sponsor submits. But also we have a vast postmarketing safety system looking at drugs that are marketed, and if we have clues that there are safety issues, then these have to be investigated, and we have conferences withnot only inside the U.S. but internationally and with the sponsors to take a look at this. So I don't want to infer that it is totally a static document here DR. HAGEY: Perhaps I could ask what's done now in the case of pregnant women in situations where perhaps safety and efficacy in pregnancy has not been established, MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc then when you do get some information, how timely is that update? DR. HIRSCHFELD: The short answer is it's variable, but there's a certain urgency that's perceived about it, and, again, I think the operative process is to make it a cooperate process. What was the source of those data? Was it picked up through postmarketing surveillance? Was it picked up through a published study? Was it picked up through anecdotal information? How reliable is it? Discussions with the sponsor would follow as soon as the signal is detected. And then there have been actuallynot only is the label updated, but there are postings on the website and in some cases "Dear Doctor" letters are sent out DR. SANTANA: Dr. Boyett? DR. BOYETT: One minor question. You interpret the words "are available" for point No. 5 as meaning that no efficacy and safety data have been received by the FDA? Is that the way that's to be interpreted? DR. HIRSCHFELD: For this particular question, correct. And this would be not because there are no data that we're unable to find, but we've requested data. And usually if people have any data, no matter what the source, MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc with the financial incentive waiting for them just to send it in, they usually manage to find whatever is available DR. SCHWEIM: As a part of old Europe, I have a question of clarification [Laughter.] DR. SCHWEIM: Steve, if I understand you correct, you said that it could happen that the company has negative data but is not willing to send it to you so you can publish it. If this is the case, it's totally opposite to the German and the European situation. If a pharmaceutical company has negative data, they must submit it. Otherwise, they will be punished by the law. So if you have indicated on a German or European package leaflet there is no data available, it means there is no data available. It does not mean that a company has negative data and doesn't present it DR. HIRSCHFELD: Right. The clarification would be if there's any safety issues, we have the authority to demand the information regarding the safety issue. That would be a public health question The concept here would be that there's an incentive for the company to provide data in any fashion, even negative data, because negative data can, nevertheless, be in the economic risk/benefit equation a highly favorable MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc undertaking. So the anticipation would be that it's likely that there are no data DR. SANTANA: I'm taking this maybe a little too far, but what would happen in a situation where you grant a waiver because, you know, you're not going to study the drug? I mean, this statement DR. HIRSCHFELD: That would be the pediatric rule, Dr. Santana, and in this case DR. SANTANA: I take it back DR. HIRSCHFELD: Okay DR. SANTANA: Further discussion on that point? DR. HIRSCHFELD: Thank you DR. SANTANA: Dr. Boyett? DR. BOYETT: I'm just trying to understand this again. This seems like a dialogue between you and a specific company, okay, so that's the only communication. Do you have blinders on? And if there's published data out there in JCO that was done by COG, you know, in some other setting, I mean, wouldn't you take advantage and use that information? DR. HIRSCHFELD: The short answer is if it's a safety concern, absolutely. If it's for other reasons, then we can askwe can make a company aware of data. Other people can submit data. And if there are datawe don't MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc have blinders, in effect. What we do, though, is we try to encourage data to be submitted so it can be verified. And the context for this question is that we and no one else apparently can identify data. There's lots of data that might exist that might be unpublished or unaccessible. But if it's publicly available data, that's certainly something that's accessible to everyone DR. SANTANA: Dr. Reynolds? DR. REYNOLDS: Steve, maybe you could clarify for us in the setting you're talking about where someone else can, quoteunquote, submit the data. What about drugs that are now off patent and that may be made by two or three different companies? I must say the Cooperative Group has data on one of those drugs. Can the Cooperative Group then submit the data, and then does the labeling take place for all companies that are making it on a generic basis? DR. HIRSCHFELD: That's a highly plausible scenario DR. SANTANA: Any other comments or points of discussion before I make a comment? [No response.] DR. SANTANA: Well, I'm not going to do a summary because we, I think, covered all the cases and the questions rather thoroughly. I just want to say again from the MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 mc pediatric oncology community how grateful we always are to the FDA to listen to what we have to say and that we think you are partners with us in this endeavor. I specifically want to thank Steve and Richard for their involvement and allowing us to express our views, as we do so well. Thank you DR. HIRSCHFELD: Thank you [Whereupon, at 2:01 p.m., the subcommittee was adjourned.] MILLER REPORTING COMPANY, INC 735 8th Street, S.E Washington, D.C. 200032802 (202) 5466666 ... prudent to recite all potential conflicts? ?of? ?interest as they apply to each participant. FDA acknowledges that there may be potential conflicts? ?of? ?interest, but because? ?of? ?the? ? general nature? ?of? ?the? ?discussion before? ?the? ?subcommittee, ... were preferred over placebo, questioning? ?the? ?ethics? ?of? ? placebo. Placebo studies were addressed in a mt? ?of? ?the? ? Pediatric? ?Subcommittee? ?of? ?the? ?AntiInfectives? ?Advisory? ? Committee? ?with a special ethical session a few years ago. ... funded by? ?the? ?Federal Government. But with? ?the? ?evolution? ?of pediatric? ?investigations and with? ?the? ?relative explosion in the? ?number? ?of? ?pediatric? ?studies and? ?the? ?varied sources? ?of? ? funding, there was a need, which was supported by many

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